This proposal seeks partial support for an international conference on Antigen Cross-presentation as part f the Gordon Research Conference series to be held in Il Ciocco, Italy from June 14-19, 2009.The broad and long-term goal to develop and promote this conference emerged from the recognition that this ubiquitous pathway of antigen uptake, transport, and presentation represented a major research area for investigators from several distinct research perspectives, each of which would be served by having a venue in which they could come together to exchange ideas and move this important field forward in the very best traditions of the Gordon Research Conferences. The subject of antigen cross presentation presents an area of investigation that cuts across several scientific fields, including: Cell Biology;Cell Death;Dendritic Cell Immunobiology;Protein Folding;Lipid Biophysics;Signal Transduction;Antigen Processing and Presentation;and Translational Research including Tumor Immunology, Autoimmunity and Host/Pathogen Interactions. We recognize the need for increased interaction across these fields and see this meeting as an opportunity to build a community and forge new collaborative efforts. Background: Cytotoxic T lymphocytes (CTLs) represent a critical component of the adaptive immune response against viruses, intracellular bacteria, and tumors through their ability to kill cells based on the proteins expressed in a target cell. To perform this task, naive CTLs must first be activated within secondary lymphoid organs by an antigen presenting cell (APC) expressing MHC class I/peptide complexes on its cell surface, causing it to undergo clonal expansion and functional differentiation. The resulting effector cells migrate to the periphery where they subsequently recognize the same peptide/MHC complexes on target cell and deliver the cytotoxic 'lethal hit'. In general, the peptides recognized on both APC and target cells are derived from antigens endogenously expressed within target cells. A long-standing paradox in immunology concerned how a professional phagocyte can prime responses against proteins expressed within a target cell. In the case of viral or bacterial infection, one might presume that the APC itself is directly infected with the same pathogen and thus can express the same genes as the infected target cell. In contrast, studies have shown that such responses are primed by uninfected APC, implying that the antigens in question must be taken up by the APC through phagocytosis, and the derived peptides somehow channeled into its own MHC class I presentation pathway, in essence crossing three membranes in the process. The same process guides the generation of effector CTL against tumors and tissue grafts, and has been referred to as 'cross-priming'while the uptake and processing of exogenous antigen for MHC I presentation by professional APC as 'cross-presentation.'The basic science aspects of how this pathway is regulated and the impact of these discoveries on disease pathogenesis and therapy is the focus of this GRC-sponsored meeting. Aims: The specific aims of this meeting are to convene 37 speakers that represent critical areas of antigen cross presentation research with a total of 135 participants for a five-day conference in a relatively isolated setting. The program will feature a keynote address and eight sessions that will broadly address current issues in the cellular and molecular biology of antigen cross presentation, the instructive role of the innate immune system in modulating the context of antigen uptake and presentation, the responsive role of the adaptive immune system in cross-tolerance versus cross-priming, and importantly, the clinical perspectives on this process. The significance of this application is that the GRC-sponsored meeting on Antigen Cross presentation is a unique The health relatedness of this application is that as the cross presentation pathway has been shown to underlie the induction and maintenance of both CD8+ T cell immunity and tolerance to the overwhelming majority of cell-associated antigens, a deeper understanding of its specific mechanisms will allow for new approaches to the immunotherapy of cancer, chronic viral diseases, and cancer, and will aid in the development of superior vaccination strategies.